This invention relates to 1,4-dideoxy-1,4-imino-L-allitol and N-substituted derivatives thereof which have glycosidase inhibitory activity. More particularly, the invention relates to a method of substantially changing the specificity of glycosidase inhibitory activity of 1,4-dideoxy-1,4-imino-L-allitol by substitution of the ring nitrogen without altering the chirality of hydroxyl groups.
It is known that polyhydroxylated pyrrolidines and piperidines provide an extensive class of powerful and specific glycosidase inhibitors. See, for example, Scofield et al., Life Sci. 39, 645-650 (1986); Elbein, Ann. Rev. Biochem. 56, 497-534 (1987); and Fleet et al., FEBS Lett. 237, 128-132 (1988). Several of these glycosidase inhibitors have been found to inhibit human immunodeficiency virus (HIV) synctium formation and virus replication, thereby indicating their potential use as antiretroviral agents. Three such compounds thus suggested as potential anti-AIDS drugs are castanospermine, 1-deoxynojirimycin (DNJ) and 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP). See, for example, Sunkara et al., Biochem. Biophys. Res. Commun. 148 (1), 206-210 (1987); Tyms et al., Lancet, Oct. 31, 1987, pp. 1025-1026; Walker et al., Proc. Natl. Acad. Sci. USA 84, 8120-8124 (1987); and Gruters et al., Nature 330, 74-77 (1987). Although the effects of these compounds may arise from their properties as specific glycosidase inhibitors, it has been shown that not all glycosidase I inhibitors are effective inhibitors of HIV as reported by Fleet et al., FEBS Lett. 237, 128-132 (1988).
Despite attempts to predict the specificity of inhibition of some of these compounds from their structure, the structural features necessary for the inhibition of a particular glycosidase cannot readily be defined. Among the factors that may determine specificity are the number and chirality of the hydroxyl groups, the ring structure and substitution of the ring nitrogen. Thus, it has been reported that alteration of the chirality of a hydroxyl group on a polyhydroxylated alkaloid generally changes the specificity of inhibition. See Molyneux et al., Arch. Biochem. Biophys. 251, 450-457 (1986); and Elbein et al., Biochemistry 26, 2502-2510 (1987). Substitution of the ring nitrogen atom usually decreases the inhibitory capacity of an alkaloid [Schweden et al., Eur. J. Biochem. 157, 563-570 (1986)] but has been shown in one case to enhance inhibition [Hettkamp et al., Ibid. 142, 85-90 (1984)]. Therefore, the actual effectiveness of a given compound as a glycosidase inhibitor or the effect on specificity by a given structural change of the compound are unpredictable.